A fast multilocus test with adaptive SNP selection for large-scale genetic-association studies

Abstract

As increasing evidence suggests that multiple correlated genetic variants could jointly influence the outcome, a multilocus test that aggregates association evidence across multiple genetic markers in a considered gene or a genomic region may be more powerful than a single-marker test for detecting susceptibility loci. We propose a multilocus test, AdaJoint, which adopts a variable selection procedure to identify a subset of genetic markers that jointly show the strongest association signal, and defines the test statistic based on the selected genetic markers. The P-value from the AdaJoint test is evaluated by a computationally efficient algorithm that effectively adjusts for multiple-comparison, and is hundreds of times faster than the standard permutation method. Simulation studies demonstrate that AdaJoint has the most robust performance among several commonly used multilocus tests. We perform multilocus analysis of over 26 000 genes/regions on two genome-wide association studies of pancreatic cancer. Compared with its competitors, AdaJoint identifies a much stronger association between the gene CLPTM1L and pancreatic cancer risk (6.0 Â 10 À8 ), with the signal optimally captured by two correlated single-nucleotide polymorphisms (SNPs). Finally, we show AdaJoint as a powerful tool for mapping cis-regulating methylation quantitative trait loci on normal breast tissues, and find many CpG sites whose methylation levels are jointly regulated by multiple SNPs nearby.

Gene-based analysis of the fibroblast growth factor receptor signaling pathway in relation to breast cancer in African American women: the AMBER consortium

“…We use a multi-locus adaptive joint test [15] as implemented in the R package AdaJoint [29]. The test identifies the best subset of SNPs that jointly show the strongest evidence for association with disease in a given gene through a variable selection procedure that takes into account the LD structure.…”

“…at least three independent signals have been identified in the FGFR2 gene [11]), the standard single SNP analysis may fail to fully capture the joint effect of multiple SNPs in a given gene [12,13]. Gene-based tests provide a powerful alternative to the single SNP approach to combine the evidence of association from several genetic variants within a gene in relation to disease [14,15]. Gene-based tests have been successfully used to identify new loci in relation to height and body mass index [12], Crohn’s disease [16], and glucose and lipid levels [17] among others.…”

Genetic variation in the insulin, insulin-like growth factor, growth hormone, and leptin pathways in relation to breast cancer in African-American women: the AMBER consortium

“…We used a multi-locus adaptive joint test 55 as implemented in the R package AdaJoint. The test identifies the best subset of SNPs that jointly show the strongest evidence for association with disease in a given gene through a variable selection procedure that takes into account the LD structure.…”

Genetic variation in the Hippo pathway and breast cancer risk in women of African ancestry

“…A noticeable limitation of previous studies is that only polymorphisms in a single candidate gene or a small subset of genes in this pathway were assessed, while some core elements of this pathway, such as LATS1/2 , were omitted . Furthermore, in addition to single‐SNP association analysis, it has been suggested that examining a group of SNPs within a biological pathway can provide complementary and valuable insights for the genetic architecture of complex diseases …”

“…1,7 Furthermore, in addition to single-SNP association analysis, it has been suggested that examining a group of SNPs within a biological pathway can provide complementary and valuable insights for the genetic architecture of complex diseases. 11,12 Considering the paucity of data on the genomic basis of disparities in breast cancer outcomes for women of African ancestry and the growing importance of Hippo pathway in breast carcinogenesis, 13 we sought to explore whether this pathway contributes to the aggressive breast cancer phenotypes observed in women of African ancestry.…”